Chroman Compound, Processes for Its Preparation, and Its Pharmaceutical Use

ABSTRACT

The present invention provided a chroman compound, the method of its preparation and pharmaceutical applications. The compound are represented by formula (I) and its pharmaceutical salt, where in :x is for O or S; n is for 2, 3 or 4; R 1  is 6-situ or 7-situ halogen, C 1-4 alkyl, C 1-4 alkyoxyl, benzyloxy, acylamino; R 2  is nitrogen-containing pentatomic or hexahydric substituted heterocyclic ring. The compound is useful to prepare anti-arrhythmic drugs, the reaction conditions of the method are mild, the raw material are plenty and easy to be obtained, and the operation and post-treatment are simple.

CROSS REFERENCE TO RELATED PATENT APPLICATION

This patent application claims the priority of the Chinese patent application No. 200610097268.7 with a filing date of Oct. 27, 2006.

FIELD OF THE INVENTION

The present invention belongs to pharmaceuticals synthesis field, relates to a chroman compound. The present invention also relates to the preparing method for such compound and its pharmaceutical use.

PRIOR ART

According to the electrophysiological effect and its mechanism of drugs obtained from Purkinje fibre in vitro experiment, the anti-arrhythmic drugs are usually classed into four groups: I—sodium channel blockade; II—β-adrenoreceptor blockade; III—agents for selective prolonging repolarization; IV—calcium antagonist. In the 1970s to the early 1980s of 20^(th) century, the developing target of anti-arrhythmic drug is based on inhibiting ventricle early contraction in the animal models or patients having PVCs after myocardial infarction. However, in recent decade, there are significant changes in treating arrhythmia by drugs. Due to the CAST experiment results, the research focus has already changed from anti-arrhythmic drugs of group I to anti-arrhythmic drugs of group III, the study on potassium ion channel blockade has been largely developed. Thereafter reported anti-arrhythmic drugs are almost potassium ion channel blockade, compared with other anti-arrhythmic drugs, they may be more safety, broad-spectrum and highly active, which are expected to be preferred anti-arrhythmic drugs.

The conventional anti-arrhythmic drugs groups III mostly block idiosyncratically rapidly activating potassium channel electric current (I_(Kr)). There are two disadvantages: leading to arrhythmia and weaken effect during rhythm of the heart expedites and stimulating β-receptor. It should be considered that due to the QT wave extends after the I_(Kr) is blocked, which consequently result in slowly activating the acutely elevated response of the potassium channel current (I_(Ks)).

In order to avoid these disadvantages, many pharmaceutical companies and institutes are engaged in developing such anti-arrhythmia drugs enabling blocking the I_(Ks) of cardiac muscle. The anti-arrhythmia drugs having I_(Kr) and I_(Ks) double blocking influence are better than selective I_(Kr) blockades in anti-arrhythmia effect. Further more, they may reduce the arrhythmia side-effect. Therefore, searching for anti-arrhythmia drugs of the group III having I_(Kr) and I_(Ks) double blocking influences, is the new hot of developing the anti-arrhythmia drugs at present.

CONTENTS OF THE INVENTION

The object to the present invention is to search for an chroman compound having double blocking influences on the rapidly activating potassium channel current (I_(Kr)) and the slowly activating potassium channel current (I_(Ks)) of delayed commutating potassium current in the potassium channel.

Another object of the present invention is to provide the method for preparing the chroman compound defined above.

Another object of the present invention is to provide the application of using such chroman compound described above in the medicaments for treating cardiovascular diseases.

The objects of the present invention will be carried out by following technical steps:

A chroman compound, described as formula (I) or its pharmaceutical salts:

in which X is O or S; n is 2, 3, or 4; R₁ is 6-situ or 7-situ halogen, C₁₋₄alkyl, C₁₋₄alkyoxyl, benzyloxy, acylamino; R₂ is nitrogenous-containing pentatomic or hexahydric substituted heterocyclic ring.

The said chroman compound where in R₂ is piperidinyl, morpholinyl, methyl piperazidinyl, N-(2-ethoxyl)piperazinyl, 1,4-iso oxazinyl, pyrrolyl, pyrazolyl or imidazolyl.

The pharmaceutical salt of the said chroman compound refers to the difumarate thereof.

A method for preparing the said chroman compound comprises the following steps:

(1) The R₁ substituted phenol is used as the starting material, reacting with 3-chloropropionic acid in the presence of KOH or NaOH for occurring substitution reaction, to syntheses intermediate compound 3-(substituted benzyloxy) propionic acid;

(2) Dissolving the 3-(substituted benzyloxy) propionic acid in polyphosphate, stirring, to obtain intermediate compound 2,3-dihydro-6(7)-R₁ substituted benzopyran-4-one;

(3) Stirring the 2,3-dihydro-6(7)-R₁ substituted chromene-4-one in refluxed HBr and glacial acetic acid, to obtain 2,3-dihydro-6(7)-hydroxylbenzopyran-4-one;

(4) Reacting 2,3-dihydro-6(7)-hydroxylbenzopyran-4-one with haloalkylane or haloaryl hydrocarbons in the presence of K₂CO₃, Na₂CO₃, or NaHCO₃ and acetonitrile or acetone, stirring at refluxing to obtain intermediate compound 2,3-dihydro-6(7)-alkoxy-R₁ substituted benzopyran-4-one or 2,3-dihydro-6(7)-benzyloxy-R₁ substituted benzopyran-4-one;

(5) Reacting 2,3-dihydro-6(7)-substituted benzopyran-4-one with compound (III) in methanol, ethanol or n-butyl alcohol as solvent, adjusting pH to the range of 3-6 by glacial acetic acid stirring at refluxing to obtain target compound of formula (I); or subsequently reacting the target compound of formula (I) with fumaric acid to obtain the difumarate of the target compound;

In which n is 2, 3 or 4; R₁ is 6-situ or 7-situ halogen, C₁₋₄alkyl, C₁₋₄alkyoxyl, benzyloxy, acylamino; R₂ is nitrogenous-containing pentatomic or hexahydric substituted heterocyclic ring.

The said chroman compound is used to preparing anti-arrhythmic medicine.

The embodiments of the present invention will be described in more details as follows:

A compound of chroman, having the structure of formula (Ia):

in which X is O or S; R₁ is 6-situ or 7-situ halogen F, Cl, or Br, or liner or branched alkyl having 1 to 4 carbon atoms or acylamino, R₂ is nitrogen-containing pentatomic or hexahydric heterocyclic ring; and n is 2, 3 or 4.

The synthesis process of formula (Ia) can be summarized as follow:

1. Preparation for the Compound of Formular (IVa):

Solid KOH and water are added to the compound (Va), which is stirred at room temperature, in the meanwhile 3-chloropropionic acid is added, then stirred and refluxed for 2 h, the resultant reaction solution is accommodated to pH for 1-2 with concentrated hydrochloric acid, extracted with ether; and then the ether layers are combined, washed with 10% NaHCO₃ aqueous solution, followed by accommodating pH for 3-4 with concentrated hydrochloric acid, and then the solid precipitated. The resultant solid is filtered, and the filter cake is recrystallized from benzene to obtain crystals in the forms of white needle.

2. Preparation for the Compound of Formula (Ia):

Polyphosphonic acid is added the compound (IVa), which is heated and stirred for 1.5 h, and then debris ice is added. The resultant mixture is extracted with ethyl acetate, the organic layer is washed with saturated NaHCO₃ aqueous solution until neutral and dried with anhydrous Na₂SO₄, concentrated, refrigerated, and then crystals precipitate. The resultant crystals are recrystallized from ethyl acetate or petroleum ether, decompressing dried at room temperature.

3. Preparation for the Compound of Formula (Ia):

Anhydrous methanol, ethanol or n-butanol and glacial acetic acid is added to the compound (Ia) and (III), the resultant mixture is stirred and refluxed. The pH of the mixture is then accommodated for almost neutral, and the mixture is extracted with chloroform, the organic layer is dried with anhydrous Na₂SO₄, and concentrated, followed by adding fumaric acid, the light yellow solid precipitate. The residue is filtered and the filter cake is recrystallized from anhydrous ethanol or anhydrous methanol.

Or, compounds having the structure of formula (Ib):

in which, X is O or S; R1 is saturated liner or branched alkyl having 1 to 4 carbon atoms or aryl; R2 is nitrogen-containing pentatomic or hexahydric substituted heterocyclic ring; n is 2, 3, or 4.

The compound of formula (Ib) can be summarized as follow:

1. The Preparation of the Compound of Formula (VIb):

Solid KOH and water is added to the compound (VIIb), which is stirred at room temperature, in the meanwhile 3-chloropropionic acid is added, then the mixture is stirred and refluxed for 2 h, the resultant reaction solution is accommodated to pH for 2 with concentrated hydrochloric acid, extracted with ether; and then the ether layers are combined, washed with 10% NaHCO₃ aqueous solution, followed by accommodating to pH for 3-4 with concentrated hydrochloric acid, and then the solid precipitate. The residue is filtered, and the filter cake is recrystallized from benzene to obtain crystals in the forms of white needle.

2. Preparation for the Compound of Formula (Vb):

Polyphosphonic acid is added to the compound (VIb), which is heated and stirred, and then debris ice is added. The resultant mixture is extracted with ethyl acetate, the organic layer is washed with 10% NaHCO₃ aqueous solution until neutral and dried with anhydrous Na₂SO₄, concentrated, refrigerated, and then white crystals precipitate. The resultant crystals are recrystallized from ethyl acetate, decompressing dried at room temperature to obtain the crystals in the forms of white needle.

3. Preparation for the Compound of Formula (IVb):

Glacial acetic acid and HBr (the concentration of hydrobromic acid by weight more than 40%) is added orderly to the compound (Vb). After the resultant reaction solution is concentrated, the mixture is then accommodated pH for 10-11 with KOH, and the mixture is further accommodated pH for 2-3 with concentrated hydrochloric acid. The resultant mixture is extracted with ethyl acetate. The organic layers are combined and dried with anhydrous Na₂SO₄, then concentrated and refrigerated, the solid precipitate. The residue is filtered and the solid is recrystallized from ethyl acetate, dried under the infraed lamp to obtain bright yellow crystals.

4. Preparation the Compound of Formula (IIb):

Alkyhalide or arylhalide hydrocarbon, and K₂CO₃, Na₂CO₃ or NaHCO₃ and acetone are added to compound (Ivb), the resultant mixture is stirred and refluxed, then washed with 10% KOH aqueous solution. The organic layer is dried with anhydrous Na₂SO₄, and then concentrated to obtain brown oil. The oil is refrigerated to precipitate white needle like crystals. The residue is filtered and recrystallized from petroleum ether, dried under the infraed lamp.

5. Preparation for the Compound of Formula (Ib):

Anhydrous ethanol (or anhydrous methanol, n-butanol) and glacial acetic acid is added to the compound (IIb) and (III), the resultant mixture is stirred and refluxed. The pH of the mixture is then accommodated for almost neutral with NaOH, and the mixture is extracted with chloroform, the organic layer is dried with anhydrous Na₂SO₄, and concentrated, followed by adding fumaric acid, the light yellow solid precipitate. The residue is filtered and the solid is recrystallized from anhydrous ethanol.

The Beneficial Effect of the Present Invention:

The chroman compounds provided according to the present invention have strong antiarrthhythmia activity, which can be used to prepare anti-arrthythmia drugs. The method for preparing such chroman compounds provided in the present invention has some advantages as which the reaction conditions are mild, the materials are enrich and easily to obtained, and the process and post treatment are simple and so on.

The Determination of Biological Activity:

Experiment title: using vitro pachynsis myocardial cells of Guinea pig, the activity is determined by the whole cell membrane Patch clamp technology.

experiment mechanism: the Guinea pig myocardial cells are separated with enzymolysis, and the rapid activation component and the slowly activation component of the delayed commutating current in the cardiac muscle cells are recorded by whole cell membrane Patch clamp. Each compound is added to the perfused liquid for measuring current after dissolved at least 10 min. The collected data is analyzed in pulsefit, the IC₅₀ for IK_(r) and IK_(s) of each compound is calculated.

1). materials and methods:

Animals: Guinea pigs, male, weight 300-400 g.

Solution: calcium free Tyrod's solution

pole inner solution (mmol/L):KCl 140, MgCl₂ 1.0, K₂-ATP 4.0, EGTA 10, HEPES 5.0, pH=7.2

2), Experiment apparatus: Patch clamp magnifier (EPC-10, Germany), inverted microscope (TE-2000U, Nikon, Japan), microelectrode puller (PIP5, Germany), micro-manipulator (PCS-5000, Burleigh, USA).

Experiment:

1. the separation of the Guinea pig myocardial cell: the Guinea pigs are stunned and their hearts are taken out to put into the calcium free Tyrode's solution, then these hearts are laid on the langendoff device after being cropped, such hearts are perfused with calcium free Tyrode's solution for 5 min, and then perfused with low calcium Tyode's solution containing type II collagenase 1 mg/mL, protease 0.1 mg/mL. BSA 0.5% and CaCl₂ 150 μmol/L until the hearts become soft and relaxed. Then, the hearts are taken off, their ventricle are cut to smash and incubated in fresh enzyme solution at 37° C., the solution is gently stirred for 5-10 min, pouring off the supernatant fluid, diluted with Tyrod's solution containing CaCl₂ 1 mmol/L, that is for the first cell stored liquor; with the same operation to obtain the second and the third cell storages. The perfused solution is saturated with 5% CO₂+95% O₂. The cells are laid for 2 h before use.

2. whole cell patch clamp technique: the cell liquor is put into the cell pool, after the cells adhere to the wall, they are perfused with outer liquor of the cells at the rate of 2 ml/min, cells that having calcium resistance and clear transverse striations are to be selected, the poles are moved to the cell surface by tridimensional manipulator. The pole top and the cell surface are formed high resistance block by underpressure, and more over using underpressure to broking cell membrane, let the pole inner liquor connected to the cell inner liquor so as to form the whole cell state. After the compensation to the capacitance and series impedance compensation the voltage tongs are recorded. The signal is led by Ag/AgCl pole and magnified by the Patch clamp magnifier, the computer dispenses presetting stimulate pulse by procedure and add to cells, and the electrical signal generated from cells is translated by transducer, and stored in computer. All of the stimulate signal control, electric current, data sampling and analyses are completed by pulse V8.60. The research use Azimilide as positive drugs, each test compound is dissolved in anhydrous ethanol, diluted to the same concentration by water, and added to outer cell liquor, the top concentration of ethanol is 0.1%. The pre-experiment result has showed that such concentration would not affect the experiment results. The drugs are administrated after the recording current has been stabilized 10 min, 10 min after the administration, the current are recorded, this experiment is proceed at 25-30° C.

3. Stimulate parameter: the record of IK_(r) and IK_(s): the back value of the either current is recorded. Using extracellular fluid containing 0.1 mmol/L CdCl₂ for perfusion, sustaining the voltage at −50 mV, depolarized to 60 mV, keeping for 500 ms, and sustaining the voltage at −50 mV, keeping for 1000 ms, recording I_(Kr); and then binding the voltage at −50 mV for 1000 ms, recording I_(Ks).

Results: compound I_(Kr)IC₅₀ (μM) I_(Ks) IC₅₀ (μM) Ia example 1 1.01 0.65 Ia example 2 4.7 0.073 Ia example 4 0.45 0.33 Ia example 5 7.47 22 Ia example 6 0.0062 61 Ia example 7 22 18.9 Ia example 8 0.54 0.0019 Ia example 9 0.619 0.304 Ia example 10 3.87 0.0058 Ib example 3 11.8 1.28 Ib example 4 0.18 0.022 Ib example 5 0.45 1.04 Ib example 6 0.4 0.0032 Ib example 7 0.0174 1.03 Ib example 9 4.34 0.0269 Ib example 10 0.106 0.0095 Ib example 11 39.7 1.23 Positive drug 0.18 0.24

As shown in the result, the chroman compounds have strong anti-arrhythmia activity, which will be used as anti-arrhythmia drugs.

EMBODIMENTS

Therein after will further describe the present invention in more details by examples which are not limited to the present invention.

General Explanation:

Melting point is measured by XT-4 type binocular micro melting point instrument (Manufactured by Peking tek Instrument limited company). IR spectra is mensurated with nicolet impact 410 type fourier Transform infrared spectrometry instrument, KBr tabletting. Elemental analysis is measured with Elementar Vario EL III type elemental analysis instrument. ¹H-NMR spectra is measured with Bruker AMX-300, ACF-300, ACF-500 type nuclear magnetic resonance apparatus, TMS as internal standard. MS spectra is measured with Agilent 6890 GC/MS and Agilent 1100 Series LC/MSD type mass spectroscope thin-layer chromatography (TLC) Board is prepared by triturating silica gel GF254 (qingdao ocean chemistry Plant) and 8% CMC Na of distilled water completely and then paving, which is activated at the temperature of 100-120° C. for 1 h to get ready for use, developed under the uviol lamp (3650 Å) or iodine. Column chromatography adopt 100-200 mesh silica gel (produced by qingdao ocean chemistry factory), wet method packing; all of the reagent are commerce chemically pure or analytically pure product, unless the special mentions, these are directly used without treating.

Examples for Compound of Formula (Ia) Example 1 1-[4-(2,3-dihydro-6-methoxy)benzopyran]imdo-3-[4-(methyl-1-piperazidine)butyl]-2,4-imidazole di:one difumarate

(1) Preparation of 3-(4-methoxyphenoxy)propanoic acid:

Solid KOH (6.80 g, 0.122 mol) and H₂O (10 ml) are added to 4-methoxyphenol (7.0 g, 0.0564 mol), the resultant mixture is stirred at the room temperature while 3-chloropropanoic acid (6.12 g, 0.0564 mol) is added to thereof. Then the mixture is stirred and heated to reflux for 3 h. The mixture is acidified to pH 2 by adding concentrated aqueous HCl and extracted with ether. The combined ether extracts is then washed with 10% aqueous NaHCO₃ and acidified to pH 3-4 by adding concentrated aqueous HCl, and precipitate was formed. The residue is filtered and recrystallized from benzene to provide needle crystal 2.0 g. m.p.: 102-103° C., yield: 18.1%.

(2) Preparation of 2,3-dihydro-6-methoxy-benzopyran-4-one:

Polyphosphonic acid (45 ml) is added to 3-(4-methoxyphenoxy) propanoic acid (2.0 g, 0.010 mol). The mixture is stirred and heated for 2 h. To the mixture, 15 g. Debris ice is added. The reaction mixture was extracted with ethyl acetate and the combined ethyl acetate extracts are washed with 10% aqueous NaHCO₃ to neutral, dried over Na₂SO₄, concentrated and cooled to provide crystal, which is recrystallized from ethyl acetate to provide white needle crystal 1.63 g. m.p.: 44-45° C., yield: 91.6%.

(3) Preparation of Title Compound

anhydrous n-butanol 10 mL and glacial acetic acid are added to 1-amino-3-[4-(4-methyl-1-piperazidine) butyl]-2,4-imidazole di:one, and then the solution of 2,3-dihydro-6-methoxybenzopyran-4-one 0.56 g (0.00316 mol) in 10 mL n-butanol is dropped. The mixture is heated to reflux for 10 hr, and then modulated the pH for 7 with NaOH, extracted with chloroform. The organic layer was dried over Na₂SO₄, concentrated and treated with fumaric acid to form precipitate. The residue is filtered and recrystallized from ethanol to provide light yellow solid 0.34 g, m.p.: 208-210° C., yield: 19.77%.

IR (KBr), cm⁻¹: 3470, 2941, 2425, 1708, 1492, 759, 753;

ESI-MS: [M+H]⁺: 430.2;

¹H-NMR (DMSO-d6), δ: 11-14 (w, 4H, 4-COOH), 7.38 (d, 1H, Ar—H), 7.02 (dd, 1H, Ar—H), 6.90 (d, 1H, Ar—H), 6.59 (s, 4H, 4×HOOC—CH═), 4.36 (s, 2H,

4.20 (t, 2H,

3.72 (s, 3H, —OCH ₃), 3.43 (t, 2H,

2.89 (t, 2H,

2.50 (s, 8H,

2.34 (t, 2H,

2.29 (s, 3H,

1.56 (m, 2H,

1.43 (m, 2H,

Example 2 1-[4-(2,3-dihydro-6-chloro) benzopyran]imdo-3-[4-(methyl-1-piperazidine) butyl]-2,4-imidazole di:one difumarate

(1) processing as the step (1) in the method of example 1, except for parachlorophenol in place of para-hydroxybenzene methyl ether, to obtain 3-[4-chlorophenoxy]propionic acid, m.p.: 135-136° C., yield: 22.58%.

(2) Processing as the step (2) in the method of example 1, using 3-[4-chlorophenoxy]propionic acid as starting material, to obtain 2,3-dihydro-6-chloro benzopyran-4-one in the forms of yellow needle crystal 3.65 g, m.p.: 100-102° C., yield: 98.6%.

(3) Processing as the step (3) in the method of example 1,2,3-dihydro-6-chloro benzopyran-4-one is reacted with 1-Amido-3-[4-(4-methyl-1-piperazidine) butyl]-2,4-imidazole di:one, to obtain the title compound in the forms of white powder 0.43 g, m.p.: 230-232° C., yield: 46.08%.

IR (KBr), cm⁻¹: 3420, 2389, 2955, 1712, 1417, 1309, 979, 763, 639; ESI-MS: [M+H]⁺: 434.2 (isotopic peak: 436.1);

¹H-NMR (DMSO-d6), δ: 10.5-14.5 (w, 4H, 4-COOH), 7.86 (s, 1H, Ar—H), 7.45 (dd, 1H, Ar—H), 7.43 (d, 1H, Ar—H), 6.58 (s, 4H, 4×HOOC—CH═), 4.39 (s, 2H,

4.28 (t, 2H,

3.43 (t, 2H,

2.90 (t, 2H,

2.50-2.58 (m, 5H,

2.49 (s, 3H,

2.38 (t, 2H,

2.32 (s, 3H,

1.55 (m, 2H,

1.44 (m, 2H,

Example 3 1-[4-(2,3-dihydro-6-methyl)benzopyran]imdo-3-[4-(methyl-1-piperazidine) butyl]-2,4-imidazole di:one difumarate

(1) processing as the step (1) in the method of example 1, except for para-methylphenol in place of para-hydroxybenzene methyl ether, to obtain 3-[4-methylphenoxy]propionic acid, m.p.: 145-147° C., yield: 10.9%.

(2) processing as the step (2) in the method of example 1, using 3-[4-methylphenoxy]propionic acid as starting material, to obtain 2,3-dihydro-6-methyl benzopyran-4-one in the forms of yellow needle crystal 3.65 g, m.p.: 100-102° C., yield: 98.6%.

(3) processing as the step (3) in the method of example 1,2,3-dihydro-6-methyl benzopyran-4-one is reacted with 1-amido-3-[4-(4-methyl-1-piperazidine)butyl]-2,4-imidazole di:one, to obtain the title compound in the forms of white powder 0.43 g, m.p.: 231-233° C., yield: 59.0%.

IR (KBr), cm⁻¹: 2948, 1719, 1298, 978, 762, 637;

ESI-MS: [M+H]⁺: 414.2; [M+Na]⁺: 436.2;

¹H-NMR (DMSO-d6), δ: 10.5-14.5 (w, 4H, 4-COOH), 7.72 (s, 1H, Ar—H), 7.23 (dd, 1H, Ar—H), 6.84 (d, 1H, Ar—H), 6.58 (s, 4H, 4×HOOC—CH═), 4.35 (s, 2H,

4.21 (t, 2H,

3.43 (t, 2H,

2.87 (t, 2H,

2.52 (s, 4H,

2.49 (s, 4H,

2.37 (t, 2H,

2.33 (s, 3H,

1.55 (m, 2H,

1.44 (m, 2H,

Example 4 1-[4-(2,3-dihydro-6-carbamino)benzopyran]imdo-+B3-[4-(methyl-1-piperazidine) butyl]-2,4-imidazole di:one difumarate

(1) processing as the step (1) in the method of example 1, except for para-carbaminophenol in place of para-hydroxybenzene methyl ether, to obtain 3-[4-nitrilephenoxy]propionic acid, m.p.: 147-149° C., yield: 29.32%.

(2) processing as the step (2) in the method of example 1, using 3-[4-nitrilephenoxy]propionic acid as starting material, to obtain 6-acylamino-2,3-dihydro-4H-1-benzopyran-4-one in the forms of light yellow sheet crystal 3.65 g, m.p.: 228-229° C., yield: 71.73%.

(3) processing as the step (3) in the method of example 1, 6-acylamino-2,3-dihydro-4H-1-benzopyran-4-one is reacted with 1-amido-3-[4-(4-methyl-1-piperazidine) butyl]-2,4-imidazole di:one, to obtain the title compound in the forms of white powder 0.20 g, m.p.: 192-194° C., yield: 16.26%.

IR (KBr), cm⁻¹: 3473, 2949, 2422, 1705, 1420, 1311, 1267, 1173, 976, 768, 637;

ESI-MS: [M+H]⁺: 443.2; [M+Na]⁺: 465.2;

¹H-NMR (DMSO-d6), δ: 8.45(s, 1H, Ar—H), 7.94 (s, 1H, —NH ₂), 7.88 (dd, 1H, Ar—H), 7.25 (s, 1H, —NH ₂), 6.98 (d, 1H, Ar—H), 6.55 (s, 8H, 8×HOOC—CH═), 4.37 (s, 2H,

4.29(t, 2H,

3.41 (t, 3H, Ar—CH ₃), 3.32 (t, 2H,

2.88 (t, 2H,

2.47-2.55 (s, 8H,

2.31-2.35 (m, 5H,

1.37-1.51 (m, 4H,

Example 5 1-[4-(2,3-dihydro-6-methoxy)benzopyran]imdo-3-(4-piperidine) butyl-2,4-imidazole di:one

processing as the method in the example 1, except for 1-amido-3-[(4-piperidine) butyl]-2,4-imidazole di:one in place of 1-amido-3-[4-(4-methyl-1-piperazidine) butyl]-2,4-imidazole di:one, to obtain the title compound in the forms of light yellow oil 0.26 g, yield: 22.41%.

IR (KBr), cm⁻¹: 2932, 1771, 1712, 1489, 1442, 1205, 1044, 756, 743;

EI-MS: m/z413: M−H

; m/z237:

m/z98(Base Peak):

¹H-NMR (CDCl₃), δ: 7.48 (d, 1H, Ar—H), 6.98 (dd, 1H, Ar—H), 6.85 (d, 1H, Ar—H), 4.31 (s, 2H,

4.26 (t, 2H,

3.80 (s, 3H, —OCH ₃), 3.57 (t, 2H,

2.96 (t, 2H,

2.44-2.550 (m, 6H,

1.63-1.70 (m, 8H,

1.26 (t, 2H,

Example 6 1-[4-(2,3-dihydro-6-chloro) benzopyran]imdo-3-(4-piperidine) butyl-2,4-imidazole di:one

processing as the method in the example 2, except for in the step (3), 1-amido-3-[(4-piperidine) butyl]-2,4-imidazole di:one in place of 1-amido-3-[4-(4-methyl-1-piperazidine) butyl]-2,4-imidazole di:one, to obtain the title compound in the forms of oil 0.20 g, yield: 17.7%.

IR (KBr), cm⁻¹: 2936, 1775, 1713, 1443, 1414, 1286, 1038, 918, 820, 734;

EI-MS: m/z417: M−H

; m/z237:

m/z98(Base Peak):

¹H-NMR (CDCl₃), δ: 7.95 (s, 1H, Ar—H), 7.27 (dd, 1H, Ar—H), 6.84 (d, 1H, Ar—H), 4.25-4.29 (m, 4H,

3.53 (t, 2H,

2.94 (t, 2H,

2.66 (d, 6H,

1.71 (m, 4H,

1.65 (m, 4H,

1.49 (s, 2H,

Example 7 1-[4-(2,3-dihydro-6-methyl)benzopyran]imdo-3-(4-piperidine) butyl-2,4-imidazole di:one

processing as the method in the example 3, except for in the step (3), 1-amido-3-[(4-piperidine) butyl]-2,4-imidazole di:one in place of 1-amido-3-[4-(4-methyl-1-piperazidine) butyl]-2,4-imidazole di:one, to obtain the title compound in the forms of oil 0.20 g, yield: 25.12%.

IR (KBr), cm⁻¹: 2934, 1770, 1712, 1492, 1443, 1414, 1298, 1220, 1041, 818, 743;

EI-MS: m/z397: M−H

; m/z237:

m/z98(Base Peak):

¹H-NMR (CDCl₃), δ: 7.79 (s, 1H, Ar—H), 7.16 (dd, 1H, Ar—H), 6.82 (d, 1H, Ar—H), 4.24-4.27 (m, 4H,

3.55 (t, 2H,

2.94 (t, 2H,

2.53(s, 4H,

2.47(t, 2H,

2.27 (s, 3H, —CH ₃), 1.61-1.68 (m, 8H,

1.46 (s, 2H, +

Example 8 1-[4-(2,3-dihydro-6-methoxy)benzopyran]imdo-3-[3-(4-methyl piperazidine-1-yl)propyl]-2,4-imidazole di:one difumarate

processing as the method in the example 1, except for in the step (3), 1-amido-3-[3-methyl-1-piperazidine) propyl]-2,4-imidazole di:one in place of 1-amido-3-[4-(4-methyl-1-piperazidine) butyl]-2,4-imidazole di:one, to obtain the title compound in the forms of white powder 0.30 g, m.p.: 220-221° C., yield: 15.46%.

IR (KBr), cm⁻¹: 2438, 1721, 1709, 1491, 1450, 1292, 1171, 1024, 977, 758, 640; EI-MS: m/z413: M−H

, m/z238:

m/z43(Base Peak): —(CH₂)₃

:

¹H-NMR (DMSO-d6), δ: 7.39 (d, 1H, Ar—H), 7.03 (dd, 1H, Ar—H), 6.90 (d, 1H, Ar—H), 6.59 (s, 4H, 4×HOOC—CH═), 4.35 (s, 2H,

4.2 0 (t, 2H,

3.72 (s, 3H, —OCH ₃), 3.45 (t, 2H,

2.86 (t, 2H,

2.35 (s, 3H,

2.34 (t, 2H,

2.28 (s, 3H,

1.70 (five, 2H,

Example 9 1-[4-(2,3-dihydro-6-methyl)benzopyran]imdo-3-[3-(4-methyl piperazidine-1-) propyl]-2,4-imidazole di:one difumarate

processing as the method in the example 1, except for in the step (3), 1-amido-3-[3-(4-methyl-1-piperazidine) propyl]-2,4-imidazole di:one in place of 1-amido-3-[4-(4-methyl-1-piperazidine) butyl]-2,4-imidazole di:one, to obtain the title compound in the forms of white thin needle crystal 0.23 g, m.p.: 237-239° C., yield 18.40%.

IR (KBr), cm⁻¹: 1775, 1709, 1447, 1411, 1301, 1174, 975, 770, 635;

EI-MS: m/z397: M−H

, m/z238:

m/z43(Base Peak): —(CH₂)₃—

;

¹H-NMR (DMSO-d6), δ: 12.5-13.5 (w, 4H, 4-COOH), 7.72 (d, 1H, Ar—H), 7.22 (dd, 1H, Ar—H), 6.85 (d, 1H, Ar—H), 6.59 (s, 4H, 4×HOOC—CH═), 4.34 (s, 2H,

4.22 (t, 2H,

3.45 (t, 2H,

2.87 (t, 2H,

2.34-2.46 (m, 6H,

2.33 (t, 2H,

2.08 (s, 6H,

Ar—CH ₃), 1.70 (m, 2H,

Example 10 1-[4-(2,3-dihydro-6-chlorine)benzopyran]imdo-3-[3-(4-methyl piperazidine-1-yl)propyl]-2,4-imidazole di:one difumarate processing as the method in the example 1, except for in the step (3), 1-amido-3-[3-(4-methyl-1-piperazidine) propyl]-2,4-imidazole di:one in place of 1-amido-3-[4-(4-methyl-1-piperazidine) butyl]-2,4-imidazole di:one, to obtain the title compound in the forms of white thin needle crystal 0.32 g, m.p.: 232-234° C., yield: 28.32%.

IR (KBr), cm⁻¹: 1709, 1412, 1302, 1289, 1175, 975, 786, 769, 636;

EI-MS: m/z417: M−H

; m/z238(Base Peak):

m/z:

m/z43: —(CH₂)₃—

;

¹H-NMR (DMSO-d6), δ: 12.5-13.5 (w, 4H, 4-COOH), 7.87 (d, 1H, Ar—H), 7.44 (dd, 1H, Ar—H), 7.02 (d, 1H, Ar—H), 6.60 (s, 4H, 4×HOOC—CH═), 4.37 (s, 2H,

4.28 (t, 2H,

3.47 (t, 2H,

2.89 (t, 2H,

2.23-2.43 (m, 13H,

1.70 (m, 2H,

Example 11 1-[4-(2,3-dihydro-7-chloro)benzopyran]imdo-3-[4-(methyl-1-piperazidine) butyl]-2,4-imidazole di:one difumarate

processing as the method in the example 1, except for in the step (1), mid-chloro phenol in place of para hydroxybenzene methyl ether, to obtain the title compound in the forms of white powder 0.53 g, yield: 46.08%.

IR (KBr), cm⁻¹: 3420, 2389, 2955, 1712, 1417, 1309, 979, 763, 639;

ESI-MS: [M+H]⁺: 434.2 (isotope peak: 436.1);

¹H-NMR (DMSO-d6), δ: 10.5-14.5 (w, 4H, 4-COOH), 7.86 (s, 1H, Ar—H), 7.45 (dd, 1H, Ar—H), 7.43 (d, 1H, Ar—H), 6.58 (s, 4H, 4×HOOC—CH═), 4.39 (s, 2H,

4.28 (t, 2H,

3.43 (t, 2H,

2.90 (t, 2H,

2.50-2.58 (m, 5H,

2.49 (s, 3_(H),

2.38 (t, 2H,

2.32 (s, 3H,

1.55 (m, 2H,

1.44 (m, 2H,

Example 12 1-[4-(2,3-dihydro-7-methyl)benzopyran]imdo-3-(2-imidazole) ethyl-2,4-imidazole di:one difumarate.

processing as the method in the example 1, except for in the step (1), mid-methyl phenol in place of para-hydroxybenzene methyl ether, to obtain the title compound in the forms of yellow oil 0.27 g, yield: 25.82% %.

IR (KBr), cm⁻¹: 2934, 1770, 1712, 1492, 1443, 1414, 1298, 1220, 1041, 818, 743;

EI-MS: m/z352: M−H

; m/z98(Base Peak):

¹H-NMR (CDCl₃), δ: 7.79 (s, 1H, Ar—H), 7.54 (m, 1H,

7.16 (dd, 1H, Ar—H), 7.01 (m, 2H,

6.82 (d, 1H, Ar—H), 4.24-4.27 (m, 4H,

3.55 (t, 2H,

2.94 (t, 2H,

2.47 (t, 2H,

Example 13 1-[4-(2,3-dihydro-6-acylamino)sulfo-benzopyran]imdo-3-[4-(methyl-1-piperazidine) butyl]-2,4-imidazole di:one difumarate

processing as the method in the example 6, using para-hydrosulphonyl benzamide as starting material, to obtain 6-acylamino-2,3-dihydro-4H-1-sulfo-benzopyran-4-one in the forms of yellow Crystal 1.97 g, yield: 75.73%.

IR (KBr), cm⁻¹: 3421, 1678, 1646, 1612, 1371, 1289, 1141, 1021, 926, 782, 611.

ESI-MS: [M+H]⁺: 192.1, [M+Na]⁺: 214.0.

To obtain the title compound of yellow powder 0.28 g, yield: 26.26%.

IR (KBr), cm⁻¹: 3473, 2949, 2422, 1705, 1420, 1311, 1267, 1173, 976, 768, 637.

ESI-MS: [M+H]⁺: 443.2; [M+Na]⁺: 465.2.

¹H-NMR (DMSO-d6), δ: 8.45(s, 1H, Ar—H), 7.94 (s, 1H, —N_H₂), 7.88 (dd, 1H, Ar—H), 7.25 (s, 1H, —NH ₂), 6.98 (d, 1H, Ar—H), 6.55 (s, 8H, 8×HOOC—CH═), 4.37 (s, 2H,

4.39(t, 2H,

3.41 (t, 3H, Ar—CH ₃), 3.32 (t, 2H,

2.98 (t, 2H,

2.47-2.55 (s, 8H,

2.31-2.35 (m, 5H,

1.37-1.51 (m, 4H,

Examples for the Compounds of Fomular (Ib) Example 14 1-[4-(2,3-dihydro-6-hydroxy)benzopyran]imdo-3-[4-(methyl-1-piperazidine) butyl]-2,4-imidazole di:one difumarate

(1) Preparation of 3-(4-methoxyphenoxy)propanoic acid:

solid KOH 6.80 g, (0.122 mol) and H₂O (10 ml) are added to para-methoxyphenol 7.0 g (0.0564 mol), the resultant mixture is stirred at the room temperature while 3-chloropropanoic acid (6.12 g, 0.0564 mol) is added to thereof. Then the mixture is stirred and heated to reflux for 3 h. The reaction solution is acidified to pH 2 by adding concentrated aqueous HCl and extracted with ether. The combined ether extracts is then washed with 10% aqueous NaHCO₃ and acidified to pH 3-4 by adding concentrated aqueous HCl, and precipitate is formed. The residue is filtered and recrystallized from benzene to provide needle crystal 2.0 g. m.p.: 102-103° C., yield: 18.1%.

(2) Preparation of 2,3-dihydro-6-methoxy-benzopyran-4-one:

polyphosphonic acid (45 ml) is added to 3-(4-methoxyphenoxy)propanoic acid 2.0 g (0.010 mol).The mixture is stirred and heated for 2 h. To the mixture, 15 g. debris ice is added. The reaction mixture was extracted with ethyl acetate and the combined ethyl acetate extracts are washed with 10% aqueous NaHCO₃ to almost neutral, dried over Na₂SO₄, concentrated and cooled to provide crystal, Which is recrystallized from ethyl acetate to provide white needle crystal 1.63 g. m.p.: 44-45° C., yield 91.6%.

(3) 2,3-dihydro-6-hydroxy benzopyran-4-one Preparation: 2,3-dihydro-6-glacial acetic acid and HBr (>40%) each 20 ml are successively added to methoxy benzopyran-4-one 2.9 g (0.0163 mol),stirred and refluxed for 1 h, and then the reactant liquor is modulated pH for 10-11 with KOH, the water layer is modulated pH for 2-3 with concentrated hydrochloric acid, and then extracted with ethyl acetate; the organic layers are combined and dried over anhydrous Na₂SO₄, cooled to precipitate black solid, and recrystallized from ethyl acetate, to obtain bright yellow crystal 2.17 g, m.p.: 142-144° C., yield: 81.2%.

(4) Preparation of title compound:

anhydrous methanol 10 mL and glacial acetic acid are added to 1-amino-3-[4-(4-methyl-1-piperazidine) butyl]-2,4-imidazole di:one 0.85 g (0.0316 mol), and then the solution of 2,3-dihydro-6-hydroxybenzopyran-4-one 0.52 g (0.00316 mol) in 10 mL methanol is dropped. The mixture is heated to reflux for 12.5 hr, and then modulated the pH for 7 with aqueous NaOH, extracted with chloroform. The organic layer is dried over Na₂SO₄, concentrated and treated with fumaric acid to form light yellow precipitate. The residue is filtered and recrystallized from anhydrous ethanol to provide white like powder 0.51 g, m.p.: 203-205° C., yield: 45.54%.

IR (KBr), cm⁻¹: 3407, 2390, 1707, 1453, 1305, 1265, 1176, 979, 763, 637.

ESI-MS: [M+H]⁺: 416.2, [M+Na]⁺: 438.1.

¹H-NMR (DMSO-d6), δ: 7.32 (d, 1H, Ar—H), 6.78-7.07 (m, 2H, Ar—H), 6.58 (s, 4H, 4×HOOC—CH═), 4.34 (s, 2H,

4.17 (t, 2H,

3.42 (t, 2H,

2.84 (t, 2H,

2.50-2.54 (m, 8H,

2.33-2.35 (m, 5H,

1.55 (m, 2H,

1.45 (m, 2H,

Example 15 1-[4-(2,3-dihydro-6-ethoxy)benzopyran]imdo-3-[4-(methyl-1-piperazidine) butyl]-2,4-imidazole di:one difumarate

(1) preparation of 2,3-dihydro-6-oxethyl benzopyran-4-one: ethyl bromide 1.66 g, K₂CO₃ 1.26 g (0.0092 mol) and acetone 50 mL are added to the 2,3-dihydro-6-hydroxybenzopyran-4-one 1.0 g (0.006 μmol) stirred and refluxed for 4 h, and then cooled to room temperature, the white like solid is filtered, and the solid is washed with 10% aqueous KOH and water. The organic layer is dried over anhydrous Na₂SO₄, concentrated and cooled to precipitate white like needle crystal. The residue is filtered and recrystallized from petroleum ether, to obtain light yellow needle crystal 0.77 g, m.p.: 60-62° C., yield: 70.94%.

(2) Preparation of title compound: processing as the method of example 14, 2,3-dihydro-6-ethoxy benzopyran-4-one is reacted with 1-amido-3-[4-(4-methyl-1-piperazidine) butyl]-2,4-imidazole di:one, to obtain white powder of the title compound 0.39 g, m.p.: 225-227° C., yield: 36.11%.

IR (KBr), cm⁻¹: 3409, 2977, 2413, 1715, 1451, 1299, 763, 638.

ESI-MS: [M+H]⁺: 444.2.

¹H-NMR (DMSO-d6), δ: 7.35 (d, 1H, Ar—H), 6.99 (dd, 1H, Ar—H), 6.87 (d, 1H, Ar—H), 6.55 (s, 4H, 4×HOOC—CH═), 4.33 (s, 2H,

4.17 (t, 2H,

3.94 (q, 2H, —OCH ₂CH₃), 3.40 (t, 2H,

2.84 (t, 2H,

2.54 (s, 5H,

2.47 (t, 2H,

2.33 (s, 3H,

1.53 (m, 2H,

1.41 (m, 2H,

1.27 (t, 3H, —OCH₂ CH ₃) ppm.

Example 16 1-[4-(2,3-dihydro-6-propoxy-)benzopyran]imdo-3-[4-(methyl-1-piperazidine) butyl]-2,4-imidazole di:one difumarate

(1) Processing as the method of example 14, except for in the step (1), bromine propane in place of ethyl bromide, to obtain light yellow solid of 2,3-dihydro-6-propoxy-benzopyran-4-one 0.67 g, m.p.: 50-52° C., yield: 67.96%.

(2) Preparation of compound: processing as the step (4) in the example 14, 2,3-dihydro-6-propoxy-benzopyran-4-ketone is reacted with 1-amido-3-[4-(4-methyl-1-piperazidine) butyl]-2,4-imidazole di:one, to obtain light yellow powder of the title compound 0.85 g, m.p.: 218-20° C., yield: 61.68%.

IR (KBr), cm⁻¹: 3484, 2965, 2425, 1714, 1448, 1299, 982, 763, 638.

ESI-MS: [M+H]⁺: 458.2.

¹H-NMR (DMSO-d6), δ: 7.35 (d, 1H, Ar—H), 7.00 (dd, 1H, Ar—H), 6.87 (d, 1H, Ar—H), 6.55 (s, 4H, 4×HOOC—CH═), 4.34 (s, 2H,

4.17 (t, 2H,

3.83 (q, 2H, —OCH ₂CH₃), 340 (t, 2H,

284 (t, 2H,

2.65 (s, 4H,

2.48 (s, 4H,

2.37 (m, 5H,

1.70 (m, 2H, —OCH₂CH₂CH₃), 1.53 (m, 2H,

1.42 (m, 2H,

0.93 (t, 3H, —OCH₂CH₂ CH ₃) ppm.

Example 17 1-[4-(2,3-dihydro-6-butoxy)benzopyran]imdo-3-[4-(methyl-1-piperazidine) butyl]-2,4-imidazole di:one difumarate

(1) Processing as the method of example 15,except for in the step (1), bromine butane in place of ethyl bromide, to obtain light yellow solid of 2,3-dihydro-6-propoxy-benzopyran-4-one 0.67 g, m.p.: 50-52° C., yield: 67.96%. Preparation of compound: processing as the step (4) in the example 14, 2,3-dihydro-6-propoxy-benzopyran-4-ketone is reacted with 1-amido-3-[4-(4-methyl-1-piperazidine) butyl]-2,4-imidazole di:one, to obtain white like powder of the title compound 0.41 g, m.p.: 208-210° C., yield: 60.35%.

IR (KBr), cm⁻¹: 3448, 2953, 1714, 1446, 1298, 1179, 637.

ESI-MS: [M+H]⁺: 472.3.

¹H-NMR (DMSO-d6), δ: 11-13 (w, 4H, —COOH), 7.38 (d, 1H, Ar—H), 7.02 (dd, 1H, Ar—H), 6.88 (d, 1H, Ar—H), 6.58 (s, 4H, 4×HOOC—CH═), 4.36 (s, 2H,

4.18 (t, 2H,

3.89 (q, 2H, —OCH ₂CH₃), 3.41 (t, 2H,

2.87 (t, 2H,

2.50 (s, 6H,

2.32 (t, 2H,

2.26 (s, 3H,

1.67 (m, 2H, —OCH₂ CH ₂CH₂CH₃), 1.43 (m, 2H,

1.41 (m, 4H,

—OCH₂CH₂ CH ₂CH₃), 0.92 (t, 3H, —OCH₂CH₂CH₂e.uns CH₃) ppm.

Example 18 1-[4-(2,3-dihydro-6-oxethyl)benzopyran]imdo-3-(4-piperidine) butyl-2,4-imidazole di:one

processing as the method in the example 14, except for in step (4), 1-amido-3-[(4-piperidine) butyl]-2,4-imidazole di:one in place of 1-amido-3-[4-(4-methyl-1-piperazidine) butyl]-2,4-imidazole di:one, to obtain light yellow oil of the title compound 0.27 g, yield: 41.34%.

IR (KBr), cm⁻¹: 2936, 1772, 1712, 1491, 1442, 1415, 1205, 1046, 961, 766, 747.

EI-MS: m/z427: M−H

; m/z237:

m/z98(Base Peak):

¹H-NMR (CDCl₃), δ: 7.46 (d, 1H, Ar—H), 6.96 (dd, 1H, Ar—H), 6.83 (d, 1H, Ar—H), 4.30 (s, 2H,

4.24 (t, 2H,

4.00 (q, 2H, —OCH ₂CH₃), 3.55 (t, 2H,

2.94 (t, 2H,

2.79 (s, 4H,

2.72(t, 2H,

1.76 (m, 4H,

1.69 (s, 4H,

1.53(t, 2H,

1.38 (t, 3H, —OCH₂ CH ₃) ppm.

Example 19 1-[4-(2,3-dihydro-6-propoxy-)benzopyran]imdo-3-(4-piperidine) butyl-2,4-imidazole di:one

processing as the method in the example 14, except for in step (4), 1-amido-3-[(4-piperidine) butyl]-2,4-imidazole di:one in place of 1-amido-3-[4-(4-methyl-1-piperazidine) butyl]-2,4-imidazole di:one, to obtain light yellow oil of the title compound 0.34 g, yield: 52.71%.

IR (KBr), cm⁻¹: 2938, 1773, 1712, 1573, 1491, 1437, 1411, 1202, 1043.

EI-MS: m/z441: M−H

; m/z237:

m/z98(Base Peak):

¹H-NMR (CDCl₃), δ: 7.54 (s, 1H, Ar—H), 6.96 (dd, 1H, Ar—H), 6.82 (d, 1H, Ar—H), 4.29 (s, 2H,

4.23 (t, 2H,

3.88 (t, 2H, —OCH ₂CH₂CH₃), 3.55 (t, 2H,

2.94 (t, 2H,

2.81 (s, 4H,

2.74 (t, 2H,

1.76 (m, 4H,

1.69 (s, 4H,

1.53 (t, 2H,

1.22 (t, 2H, —OCH₂ CH ₂CH₃), 0.99 (t, 3H, —OCH₂CH₂ CH ₃) ppm.

Example 20 1-[4-(2,3-dihydro-6-butoxy)benzopyran]imdo-3-(4-piperidine) butyl-2,4-imidazole di:one

processing as the method in the example 14, except for in step (4) 1-amido-3-[(4-piperidine) butyl]-2,4-imidazole di:one in place of 1-amido-3-[4-(4-methyl-1-piperazidine) butyl]-2,4-imidazole di:one, to obtain light yellow oil of the title compound 0.51 g, yield: 56.04%.

IR (KBr), cm⁻¹: 2934, 1774, 1712, 1596, 1489, 1441, 1413, 1204, 1042, 822, 768.

EI-MS: m/z455: M−H

; m/z237:

m/z98(Base Peak):

¹H-NMR (CDCl₃), δ: 7.44 (s, 1H, Ar—H), 6.94 (dd, 1H, Ar—H), 6.82 (d, 1H, Ar—H), 4.28 (s, 2H,

4.23 (t, 2H,

3.92 (t, 2H, —OCH ₂CH₂CH₂CH₃), 3.55 (t, 2H,

2.92 (t, 2H,

2.81 (s, 4H,

2.74 (t 2H,

1.46-1.72 (m, 10H,

1.19-1.22 (m, 4H, —OCH₂ CH ₂ CH ₂CH₃), 0.93 (t, 3H, —OCH₂CH₂ CH ₃) ppm.

Example 21 1-[4-(2,3-dihydro-6-hydroxy)benzopyran]imdo-3-(4-piperidine) butyl-2,4-imidazole di:one

processing as the method in the example 14, except for in step (4) 1-amido-3-[(4-piperidine) butyl]-2,4-imidazole di:one in place of 1-amido-3-[4-(4-methyl-1-piperazidine) butyl]-2,4-imidazole di:one, to obtain light yellow oil of the title compound 0.46 g, yield: 38.3%.

IR (KBr), cm⁻¹: 3556, 2937, 1774, 1713, 1594, 1446, 1413, 1040, 911, 823, 731.

EI-MS: m/z400: M

; m/z237:

m/z98(Base Peak):

¹H-NMR (CDCl₃), δ: 7.40 (s, 1H, Ar—H), 6.92 (dd, 1H, Ar—H), 6.77 (d, 1H, Ar—H), 4.5-6.0 (w, 1H, —OH), 4.26 (s, 2H,

4.20 (t, 2H,

3.53 (t, 2H,

2.90 (t, 2H,

2.89 (s, 4H,

2.71 (t, 2H,

1.66-1.83 (m, 6H,

1.64 (m, 2H,

1.60(s, 2H,

Example 22 1-[4-(2,3-dihydro-6-oxethyl)benzopyran]imdo-3-[3-(4-methyl piperazidine-1-group)propyl]-2,4-imidazole di:one difumarate

processing as the method in the example 14, except for in step (4), 1-amido-3-[3-(4-methyl-1-piperazidine) propyl]-2,4-imidazole di:one in place of 1-amido-3-[4-(4-methyl-1-piperazidine) butyl]-2,4-imidazole di:one, to obtain white loose powder of the title compound 0.35 g, yield: 19.55%.

IR (KBr), cm⁻¹: 2984, 1775, 1720, 1710, 1493, 1452, 1292, 1178, 977, 763, 640.

EI-MS: m/z428: M−H

, m/z238:

m/z43(Base Peak): —(CH₂)₃—

.

¹H-NMR (DMSO-d6), δ: 7.39 (d, 1H, Ar—H), 7.02 (dd, 1H, Ar—H), 6.88 (d, 1H, Ar—H), 6.59 (s, 4H, 4×HOOC—CH═), 4.35 (s, 2H,

4.20 (t, 2H,

3.95 (q, 3H, —OCH ₂CH₃), 3.47 (t, 2H,

2.87 (t, 2H,

2.53 (s, 4H,

2.49 (s, 4H,

2.35 (t, 2H,

2.29 (s, 3H,

1.72 (m, 2H,

1.30 (t, 3H, —OCH₂ CH ₃) ppm.

Example 23 1-[4-(2,3-dihydro-6-propoxy-)benzopyran]imdo-3-[3-(4-methyl piperazidine-1-yl)propyl]-2,4-imidazole di:one difumarate

processing as the method in the example 14, except for in step (4), 1-amido-3-[3-(4-methyl-1-piperazidine)propyl]-2,4-imidazole di:one in place of 1-amido-3-[4-(4-methyl-1-piperazidine) butyl]-2,4-imidazole di:one, to obtain white loose powder of the title compound 0.43 g, yield: 26.54%.

IR (KBr), cm⁻¹: 2963, 2389, 1776, 1722, 1711, 1449, 1288, 1178, 976, 788, 758, 638.

EI-MS: m/z442: M−H

, m/z238:

m/z43(Base Peak): —(CH₂)₃—

.

¹H-NMR (DMSO-d6), δ: 12.5-13.5 (w, 4H, 4-COOH), 7.39 (d, 1H, Ar—H), 7.02 (dd, 1H, Ar—H), 6.88 (d, 1H, Ar—H), 6.59 (s, 4H, 4×HOOC—CH═), 4.35 (s, 2H,

4.20 (t, 2H,

3.86 (t, 2H, —OCH ₂CH₂CH₃), 3.46 (t, 2H,

2.87 (t, 2H,

2.34-2.43 (m, 6H,

2.26 (s, 3H,

1.70 (m, 2H,

1.26 (m, 2H, —OCH₂ CH ₂CH₃), 0.96 (t, 3H, —OCH₂CH₂ CH ₃) ppm.

Example 24 1-[4-(2,3-dihydro-6-butoxy)benzopyran]imdo-3-[3-(4-methyl piperazidine-1-yl)propyl]-2,4-imidazole di:one difumarate

processing as the method in the example 14, except for in step (4), 6-amido-3-[3-(4-methyl-1-piperazidine) propyl]-2,4-imidazole di:one in place of 1-amido-3-[4-(4-methyl-1-piperazidine) butyl]-2,4-imidazole di:one, to obtain white loose powder of the title compound 0.35 g, yield: 25.40%.

IR (KBr), cm⁻¹: 2959, 2389, 1776, 1722, 1711, 1450, 1292, 1179, 977, 788, 765, 640.

EI-MS: m/z456: M−H

, m/z238(Base Peak):

m/z43: —(CH₂)₃—

.

¹H-NMR (DMSO-d6), δ: 12.5-13.5 (w, 4H, 4-COOH), 7.39 (d, 1H, Ar—H), 7.02 (dd, 1H, Ar—H), 6.88 (d, 1H, Ar—H), 6.60 (s, 4H, 4×HOOC—CH═), 4.35 (s, 2H,

4.20 (t, 2H,

3.90 (t, 2H, —OCH ₂CH₂CH₃), 3.46 (t, 2H,

2.87 (t, 2H,

2.34-2.43 (m, 8H,

2.33(t, 2H,

2.25 (s, 3H,

1.67 (m, 4H,

—OCH₂ CH ₂CH₂CH₃), 1.42 (m, 2H, —OCH₂CH₂ CH ₂CH₃), 0.92 (t, 3H, —OCH₂CH₂CH₂ CH ₃) ppm.

Example 25 1-[4-(2,3-dihydro-7-benzyloxy-)benzopyran]imdo-3-(4-pyrrole) butyl-2,4-imidazole di:one

processing as the method in the example 14, except for in step (4), 1-amido-3-[4-(1-pyrrole) butyl]-2,4-imidazole di:one in place of 1-amido-3-[4-(4-methyl-1-piperazidine) butyl]-2,4-imidazole di:one, to obtain yellow solid of (2,3-dihydro-7-benzyloxy-)benzopyran 0.76 g, yield: 56.88%. to obtain light yellow oil of the title compound 0.51 g, yield: 56.04%

IR (KBr), cm⁻¹: 2934, 1774, 1712, 1596, 1489, 1441, 1413, 1204, 1042, 822, 768.

EI-MS: m/z471: M−H

; m/z98(Base Peak):

¹H-NMR (CDCl₃), δ: 7.44 (s, 1H, Ar—H), 7.19 (m, 5H, Ar—H), 6.94 (dd, 1H, Ar—H), 6.82 (d, 1H, Ar—H), 6.46 (d, 2H,

5.93 (d, 2H,

4.28 (s, 2H,

4.23 (t, 2H,

3.92 (t, 2H, —OCH ₂Ar), 3.55 (t, 2H,

2.92 (t, 2H,

2.74 (t, 2H,

1.72 (m, 4H,

Example 26 1-[4-(2,3-dihydro-6-hydroxy)sulfo-benzopyran]imdo group-3-(4-(4-(2-hydroxy ethyl)piperazidine)-1-group)butyl-2,4-imidazole di:one

processing as the method in the example 14, except for para-hydrosulphonyl benzamide in place of para hydroxybenzene methyl ether, to prepare 2,3-dihydro-6-hydroxy sulfo-benzopyran 1.2 g. yield: 65.12%; in Step (4), 1-amido-3-[4-(4-ethoxy]piperazidine) butyl]-2,4-imidazole di:one in place of 1-amido-3-[4-(4-methyl-1-piperazidine) butyl]-2,4-imidazole di:one, to obtain light yellow oil of the title compound 0.56 g, yield: 38.39%.

IR (KBr), cm⁻¹: 3556, 2937, 1774, 1713, 1594, 1446, 1413, 1040, 911, 823, 731.

EI-MS: m/z461: M

; m/z98(Base Peak):

¹H-NMR (CDCl₃), δ: 7.40 (s, 1H, Ar—H), 6.92 (dd, 1H, Ar—H), 6.77 (d, 1H, Ar—H), 4.5-6.0 (w, 1H, —OH), 4.26 (s, 2H,

4.20 (t, 2H,

3.63 (t, 2H, N—CH₂ CH ₂OH), 3.53 (t, 2H,

2.90 (t, 2H,

2.71 (t, 2H,

2.55 (t, 2H, N—CH ₂CH₂OH), 2.46 (s, 8H,

1.64 (m, 2H,

1.60 (s, 2H, 

1. A chroman compound of formula (I) or its pharmaceutical salts:

in which X is O or S; n is 2, 3, or 4; R₁ is 6-situ or 7-situ halogen, C₁₋₄alkyl, C₁₋₄alkyoxyl, benzyloxy, acylamino; R₂ is nitrogen-containing pentatomic or hexahydric substituted heterocyclic ring.
 2. The chroman compound according to claim 1, characterized in that R₂ is piperidinyl, morpholinyl, methyl piperazidinyl, N-(2-ethoxyl)piperazinyl, 1,4-iso oxazinyl, pyrrolyl, pyrazolyl or imidazolyl.
 3. The chroman compound according to claim 1, characterized in that its pharmaceutical salt is a difumarate thereof.
 4. A method for preparing the chroman compound according to claim 1, characterized in which comprises the following steps: (1) The R₁ substituted phenol as the starting material, reacting with 3-chloropropionic acid in the presence of KOH or NaOH for occurring substitution reaction, to synthesize intermediate compound 3-(substituted benzyloxy)propionic acid; (2) Dissolving the 3-(substituted benzyloxy)propionic acid in polyphosphate, stirring, to obtain intermediate compound 2,3-dihydro-6(7)-R₁ substituted benzopyran-4-one; (3) Stirring the 2,3-dihydro-6(7)-R₁ substituted chromene-4-one in the refluxed HBr and glacial acetic acid, to obtain 2,3-dihydro-6(7)-hydroxyl benzopyran-4-one; (4) Reacting 2,3-dihydro-6(7)-hydroxylbenzopyran-4-one with haloalkylane or haloaryl hydrocarbons in the presence of K₂CO₃, Na₂CO₃, or NaHCO₃ and acetonitrile or acetone, stirring under refluxing to obtain intermediate compound 2,3-dihydro-6(7)-alkoxy-R₁ substituted benzopyran-4-one or 2,3-dihydro-6(7)-benzyloxy-R₁ substituted benzopyran-4-one; (5) Reacting 2,3-dihydro-6(7)-substituted benzopyran-4-one with compound (III) in methanol, ethanol or n-butyl alcohol as solvent, adjusting pH to the range of 3-6 by glacial acetic acid, stirring under refluxing to obtain target compound of formula (I); or subsequently reacting the target compound of formula (I) with fumaric acid to obtain the difumarate of the target compound;

In which n is 2, 3 or 4; R₁ is 6-situ or 7-situ halogen, C₁₋₄alkyl, C₁₋₄alkyoxyl, benzyloxy, acylamino; R₂ is nitrogen-containing pentatomic or hexahydric substituted heterocyclic ring.
 5. Applying a chroman compound described in claim 1 for preparing anti-arrhythmic medicine. 